Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist.

Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

Experiences of a digital health intervention for young people exposed to technology assisted sexual abuse: a qualitative study.

BACKGROUND: There is growing evidence that Technology Assisted Sexual Abuse (TASA) represents a serious problem for large numbers of children. To date, there are very few evidence-based interventions available to young people (YP) after they have been exposed to this form of abuse, and access to support services remains a challenge. Digital tools such as smartphones have the potential to increase access to mental health support and may provide an opportunity for YP to both manage their distress and reduce the possibility of further victimization. The current study explores the acceptability of a digital health intervention (DHI; the i-Minds app) which is a theory-driven, co-produced, mentalization-based DHI designed for YP aged 12-18 who have experienced TASA. METHODS: Semi-structured interviews were conducted with 15 YP recruited through Child and Adolescent Mental Health Services, a Sexual Assault Referral Centre and an e-therapy provider who had access to the i-Minds app as part of a feasibility clinical trial. Interviews focused on the acceptability and usability of i-Minds and were coded to themes based on the Acceptability of Healthcare Interventions framework. RESULTS: All participants found the i-Minds app acceptable. Many aspects of the app were seen as enjoyable and useful in helping YP understand their abuse, manage feelings, and change behavior. The app was seen as usable and easy to navigate, but for some participants the level of text was problematic and aspects of the content was, at times, emotionally distressing at times. CONCLUSIONS: The i-Minds app is useful in the management of TASA and helping change some risk-related vulnerabilities. The app was designed, developed and evaluated with YP who had experienced TASA and this may account for the high levels of acceptability seen. TRIAL REGISTRATION: The trial was registered on the ISRCTN registry on the 12/04/2022 as i-Minds: a digital intervention for young people exposed to online sexual abuse (ISRCTN43130832).

Cost per Patient Achieving Treatment Targets and Number Needed to Treat with Tirzepatide Versus Semaglutide 1 mg in Patients with Type 2 Diabetes in the United States.

INTRODUCTION: Achieving glycemic control can help reduce complications of type 2 diabetes (T2D). This study compared the pharmacy cost per responder and number needed to treat (NNT) of tirzepatide 5 mg, 10 mg, and 15 mg versus semaglutide 1 mg to achieve glycemic, weight loss, and composite treatment endpoints in patients with T2D in the United States. METHODS: The proportions of patients achieving glycemic, weight loss, and composite treatment endpoints were obtained from the phase 3 SURPASS-2 randomized clinical trial which compared tirzepatide 5 mg, 10 mg, and 15 mg to semaglutide 1 mg. Annual pharmacy costs were calculated using 2022 wholesale acquisition costs. Cost per responder and NNT were calculated along with 95% confidence intervals and tests for statistical significance (P ≤ 0.05). RESULTS: Tirzepatide had a lower cost per responder to achieve glycated hemoglobin A1c (HbA1c) endpoints of ≤ 6.5% (10 mg and 15 mg doses) and < 5.7% (all doses) and weight loss endpoints of ≥ 5% (10 mg and 15 mg doses), ≥ 10% (all doses), and ≥ 15% (all doses). The cost per responder to achieve HbA1c < 7% (all doses of tirzepatide) and ≤ 6.5% (5 mg tirzepatide) were not statistically significantly different between tirzepatide and semaglutide 1 mg. The cost per patient to achieve the composite endpoints (HbA1c < 7.0%, ≤ 6.5%, or < 5.7%/weight loss ≥ 10%/no hypoglycemia) was statistically significantly lower for all doses of tirzepatide than for semaglutide 1 mg. The NNTs for all doses of tirzepatide were statistically significantly lower than that for semaglutide 1 mg to achieve all individual and composite endpoints, with the exception of the 5 mg dose for HbA1c < 7.0% and HbA1c ≤ 6.5%, where tirzepatide had numerically lower NNTs that were not statistically significant. CONCLUSION: Tirzepatide is a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) that may offer the potential to achieve stringent glycemic goals, weight loss targets, and composite treatment goals at a lower cost per responder compared to semaglutide 1 mg among people with T2D.

Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function.

Plant homeodomain fingers (PHD-fingers) are a family of reader domains that can recruit epigenetic proteins to specific histone modification sites. Many PHD-fingers recognise methylated lysines on histone tails and play crucial roles in transcriptional regulation, with their dysregulation linked to various human diseases. Despite their biological importance, chemical inhibitors for targeting PHD-fingers are very limited. Here we report a potent and selective de novo cyclic peptide inhibitor (OC9) targeting the Nε-trimethyllysine-binding PHD-fingers of the KDM7 histone demethylases, developed using mRNA display. OC9 disrupts PHD-finger interaction with histone H3K4me3 by engaging the Nε-methyllysine-binding aromatic cage through a valine, revealing a new non-lysine recognition motif for the PHD-fingers that does not require cation-π interaction. PHD-finger inhibition by OC9 impacted JmjC-domain mediated demethylase activity at H3K9me2, leading to inhibition of KDM7B (PHF8) but stimulation of KDM7A (KIAA1718), representing a new approach for selective allosteric modulation of demethylase activity. Chemoproteomic analysis showed selective engagement of OC9 with KDM7s in T cell lymphoblastic lymphoma SUP T1 cells. Our results highlight the utility of mRNA-display derived cyclic peptides for targeting challenging epigenetic reader proteins to probe their biology, and the broader potential of this approach for targeting protein-protein interactions.

Intestinal bile acids provide a surmountable barrier against C. difficile TcdB-induced disease pathogenesis.

Intestinal bile acids play an essential role in the Clostridioides difficile lifecycle having been shown in vitro to modulate various aspects of pathogenesis, including spore germination, vegetative growth, and more recently the action of the primary virulence determinant, TcdB. Here, we investigated whether physiological levels of the total pool of intestinal bile acids in mice and humans protect against TcdB action. Small molecules extracted from the lumenal contents of the small intestine, cecum, colon, and feces were found to inhibit TcdB in accordance with the differential amounts of total bile acids in each compartment. Extracts from antibiotic-treated and germ-free mice, despite harboring dramatically altered bile acid profiles, unexpectedly also prevented TcdB-induced cell rounding to similar extents. We show that protection, however, is surmountable and can be overcome at higher doses of TcdB-typical to those seen during severe C. difficile infection-suggesting that the protective properties of intestinal bile acids are operant primarily under low to moderate toxin levels. Taken together, these findings demonstrate a role for intestinal bile acids in attenuating virulence, provide insights into asymptomatic carriage of toxigenic C. difficile, and inform strategies to manipulate bile acid levels for therapeutic benefit.

Scale-Up of HIV Antiretroviral Therapy and Estimation of Averted Infections and HIV-Related Deaths - Uganda, 2004-2022.

On January 28, 2003, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), the largest commitment by any nation to address a single disease in history, was announced.* In April 2004, the first person in the world to receive PEPFAR-supported antiretroviral therapy (ART) was a man aged 34 years in Uganda. Effective ART reduces morbidity and mortality among persons with HIV infection (1) and prevents both mother-to-child transmission (MTCT) (2) and sexual transmission once viral load is suppressed to undetectable levels (<200 viral copies/mL) (3). By September 2022, more than 1.3 million persons with HIV infection in Uganda were receiving PEPFAR-supported ART, an increase of approximately 5,000% from September 2004. As indicators of the ART program's effectiveness, a proxy MTCT rate decreased 77%, from 6.4% in 2010 to 1.5% in 2022, and the viral load suppression rate (<1,000 viral copies/mL) increased 3%, from 91% in 2016 to 94% in September 2022. During 2004-2022, ART scale-up helped avert nearly 500,000 HIV infections, including more than 230,000 infections among HIV-exposed infants, and approximately 600,000 HIV-related deaths. Going forward, efforts will focus on identifying all persons with HIV infection and rapidly linking them to effective ART. PEPFAR remains committed to continued strong partnership with the Government of Uganda, civil society, and other development partners toward sustainable solutions aligned with the Joint United Nations Programme on HIV/AIDS (UNAIDS) fast-track strategy to ending the global AIDS epidemic by 2030† and safeguarding impact achieved in the long term.

Development of a Positive Psychology Well-Being Intervention in a Community Pharmacy Setting.

Background: Community pharmacies are well-placed to deliver well-being interventions; however, to date, nothing has been produced specifically for this setting. The aim of this study was to develop a positive psychology intervention suitable for a community pharmacy setting with the goal of increasing the well-being of community members. Methods: Intervention development consisted of three steps: Step 1-identify the evidence-base and well-being model to underpin the basis of the intervention (Version 1); Step 2-model the intervention and gather user feedback to produce Version 2, and Step 3-revisit the evidence-base and refine the intervention to produce Version 3. Results: Findings from nine studies (seven RCTs, one cross-sectional, one N-1 design plus user feedback were applied to model a 6-week 'Prescribing Happiness (P-Hap)' intervention, underpinned by the PERMA model plus four other components from the positive psychology literature (Three Good Things, Utilising Your Signature Strengths in New Ways, Best Possible Selves and Character Strengths). A PERMA-based diary was designed to be completed 3 days a week as part of the intervention. Conclusions: This work is an important development which will direct the future implementation of interventions to support well-being in this novel setting. The next stage is to gain the perspectives of external stakeholders on the feasibility of delivering the P-Hap for its adoption into community pharmacy services in the future.

Excellent treatment outcomes from low dose radiation therapy for primary cutaneous CD4+ small/medium T-Cell lymphoproliferative disorder.

BACKGROUND AND PURPOSE: Primary cutaneous CD4 + small/medium T-cell lymphoproliferative disorder (PCSMLPD) is a benign behaving condition, typically manifesting as solitary head or neck papules, frequently creating cosmetic concerns. Optimal management of this rare disease is unclear. Herein, patterns of care and treatment outcomes are described, with particular focus on low-dose RT. MATERIALS AND METHODS: Eligibility required biopsy-proven PCSMLPD on central review, diagnosed between 2007-2022. Patterns of care, treatment responses and relapse patterns were assessed. Freedom-from-progression (FFP) was compared between RT and surgery. RESULTS: 41 patients were eligible. First-line treatments were: RT, 19 (46.3 %); surgery, 17 (41.5 %) (3 received adjuvant RT); watchful waiting, 5 (12.2 %). Median follow-up was 37.7 months. Overall, 24 patients received RT (19 definitive first-line, 3 adjuvant, 2 second-line). 10 (42 %) received 4 Gy in 2 fractions (with no acute toxicities); 14 (58 %) received 20-40 Gy. Complete response rate was 100 %. No post-RT relapses observed. After first-line surgery alone (n = 14, 3 with positive margins), 4 (28.5 %) experienced relapse (2 local, 2 distant). Watchful-waiting (n = 5) led to partial resolution post-biopsy in 4 patients; no complete resolution seen. 3-year FFP for RT alone was 100 % vs 61 % for surgery alone (p = 0.12). CONCLUSION: RT is a successful, non-invasive option for PCSMLPD: 100 % achieved complete response, with no relapses, and FFP appearing numerically superior to surgery in this cohort. In this first series of low-dose RT for PCSMLPD, 4 Gy in 2 fractions appears an excellent treatment option, offering durable disease control, no acute toxicities and convenient treatment time of only 2 days.

Progress towards the UNAIDS 90-90-90 targets among persons aged 50 and older living with HIV in 13 African countries.

INTRODUCTION: Achieving optimal HIV outcomes, as measured by global 90-90-90 targets, that is awareness of HIV-positive status, receipt of antiretroviral (ARV) therapy among aware and viral load (VL) suppression among those on ARVs, respectively, is critical. However, few data from sub-Saharan Africa (SSA) are available on older people (50+) living with HIV (OPLWH). We examined 90-90-90 progress by age, 15-49 (as a comparison) and 50+ years, with further analyses among 50+ (55-59, 60-64, 65+ vs. 50-54), in 13 countries (Cameroon, Cote d'Ivoire, Eswatini, Ethiopia, Kenya, Lesotho, Malawi, Namibia, Rwanda, Tanzania, Uganda, Zambia and Zimbabwe). METHODS: Using data from nationally representative Population-based HIV Impact Assessments, conducted between 2015and 2019, participants from randomly selected households provided demographic and clinical information and whole blood specimens for HIV serology, VL and ARV testing. Survey weighted outcomes were estimated for 90-90-90 targets. Country-specific Poisson regression models examined 90-90-90 variation among OPLWH age strata. RESULTS: Analyses included 24,826 HIV-positive individuals (15-49 years: 20,170; 50+ years: 4656). The first, second and third 90 outcomes were achieved in 1, 10 and 5 countries, respectively, by those aged 15-49, while OPLWH achieved outcomes in 3, 13 and 12 countries, respectively. Among those aged 15-49, women were more likely to achieve 90-90-90 targets than men; however, among OPLWH, men were more likely to achieve first and third 90 targets than women, with second 90 achievement being equivalent. Country-specific 90-90-90 regression models among OPLWH demonstrated minimal variation by age stratum across 13 countries. Among OLPWH, no first 90 target differences were noted by age strata; three countries varied in the second 90 by older age strata but not in a consistent direction; one country showed higher achievement of the third 90 in an older age stratum. CONCLUSIONS: While OPLWH in these 13 countries were slightly more likely than younger people to be aware of their HIV-positive status (first 90), this target was not achieved in most countries. However, OPLWH achieved treatment (second 90) and VL suppression (third 90) targets in more countries than PLWH <50. Findings support expanded HIV testing, prevention and treatment services to meet ongoing OPLWH health needs in SSA.

Correcting for selection bias in HIV prevalence estimates: an application of sample selection models using data from population-based HIV surveys in seven sub-Saharan African countries.

INTRODUCTION: Population-based biomarker surveys are the gold standard for estimating HIV prevalence but are susceptible to substantial non-participation (up to 30%). Analytical missing data methods, including inverse-probability weighting (IPW) and multiple imputation (MI), are biased when data are missing-not-at-random, for example when people living with HIV more frequently decline participation. Heckman-type selection models can, under certain assumptions, recover unbiased prevalence estimates in such scenarios. METHODS: We pooled data from 142,706 participants aged 15-49 years from nationally representative cross-sectional Population-based HIV Impact Assessments in seven countries in sub-Saharan Africa, conducted between 2015 and 2018 in Tanzania, Uganda, Malawi, Zambia, Zimbabwe, Lesotho and Eswatini. We compared sex-stratified HIV prevalence estimates from unadjusted, IPW, MI and selection models, controlling for household and individual-level predictors of non-participation, and assessed the sensitivity of selection models to the copula function specifying the correlation between study participation and HIV status. RESULTS: In total, 84.1% of participants provided a blood sample to determine HIV serostatus (range: 76% in Malawi to 95% in Uganda). HIV prevalence estimates from selection models diverged from IPW and MI models by up to 5% in Lesotho, without substantial precision loss. In Tanzania, the IPW model yielded lower HIV prevalence estimates among males than the best-fitting copula selection model (3.8% vs. 7.9%). CONCLUSIONS: We demonstrate how HIV prevalence estimates from selection models can differ from those obtained under missing-at-random assumptions. Further benefits include exploration of plausible relationships between participation and outcome. While selection models require additional assumptions and careful specification, they are an important tool for triangulating prevalence estimates in surveys with substantial missing data due to non-participation.

Hybrid extracellular vesicles-liposome incorporated advanced bioink to deliver microRNA.

In additive manufacturing, bioink formulations govern strategies to engineer 3D living tissues that mimic the complex architectures and functions of native tissues for successful tissue regeneration. Conventional 3D-printed tissues are limited in their ability to alter the fate of laden cells. Specifically, the efficient delivery of gene expression regulators (i.e. microRNAs (miRNAs)) to cells in bioprinted tissues has remained largely elusive. In this study, we explored the inclusion of extracellular vesicles (EVs), naturally occurring nanovesicles (NVs), into bioinks to resolve this challenge. EVs show excellent biocompatibility, rapid endocytosis, and low immunogenicity, which lead to the efficient delivery of miRNAs without measurable cytotoxicity. EVs were fused with liposomes to prolong and control their release by altering their physical interaction with the bioink. Hybrid EVs-liposome (hEL) NVs were embedded in gelatin-based hydrogels to create bioinks that could efficiently encapsulate and deliver miRNAs at the target site in a controlled and sustained manner. The regulation of cells' gene expression in a 3D bioprinted matrix was achieved using the hELs-laden bioink as a precursor for excellent shape fidelity and high cell viability constructs. Novel regulatory factors-loaded bioinks will expedite the translation of new bioprinting applications in the tissue engineering field.

Food insecurity and the risk of HIV acquisition: findings from population-based surveys in six sub-Saharan African countries (2016-2017).

OBJECTIVE: To assess the potential bidirectional relationship between food insecurity and HIV infection in sub-Saharan Africa. DESIGN: Nationally representative HIV impact assessment household-based surveys. SETTING: Zambia, Eswatini, Lesotho, Uganda and Tanzania and Namibia. PARTICIPANTS: 112 955 survey participants aged 15-59 years with HIV and recency test results. MEASURES: Recent HIV infection (within 6 months) classified using the HIV-1 limited antigen avidity assay, in participants with an unsuppressed viral load (>1000 copies/mL) and no detectable antiretrovirals; severe food insecurity (SFI) defined as having no food in the house ≥three times in the past month. RESULTS: Overall, 10.3% of participants lived in households reporting SFI. SFI was most common in urban, woman-headed households, and in people with chronic HIV infection. Among women, SFI was associated with a twofold increase in risk of recent HIV infection (adjusted relative risk (aRR) 2.08, 95% CI 1.09 to 3.97). SFI was also associated with transactional sex (aRR 1.28, 95% CI 1.17 to 1.41), a history of forced sex (aRR 1.36, 95% CI 1.11 to 1.66) and condom-less sex with a partner of unknown or positive HIV status (aRR 1.08, 95% CI 1.02 to 1.14) in all women, and intergenerational sex (partner ≥10 years older) in women aged 15-24 years (aRR 1.23, 95% CI 1.03 to 1.46). Recent receipt of food support was protective against HIV acquisition (aRR 0.36, 95% CI 0.14 to 0.88). CONCLUSION: SFI increased risk for HIV acquisition in women by twofold. Heightened food insecurity during climactic extremes could imperil HIV epidemic control, and food support to women with SFI during these events could reduce HIV transmission.

Work and health challenges of Indigenous people in Canada.

The Truth and Reconciliation Commission of Canada has published 94 calls to action to redress the legacy of residential schools where thousands of Indigenous children have died. The objective of this narrative review is to address some of these calls by summarising the available evidence on work and health issues encountered by Indigenous workers in Canada. We searched seven databases to retrieve studies on Indigenous people, in Canada, and on occupational health as defined by the International Labour Organization. We included 31 studies, from which we found that Indigenous workers are experiencing intersectionality issues: in addition to having differential health issues related to a below-average socioeconomic status, Indigenous workers face discrimination in workplaces that affects their mental health. Indigenous workers might also cumulate occupational and environmental exposures from industries that have settled close to their dwellings (eg, exposure to polychlorobiphenyls). There is a scarcity of studies on major occupational health topics such as occupational cancers or musculoskeletal disorders in Indigenous people.

Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction.

Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.

Trends of notification rates and treatment outcomes of tuberculosis cases with and without HIV co-infection in eight rural districts of Uganda (2015 - 2019).

BACKGROUND: The End TB Strategy aims to reduce new tuberculosis (TB) cases by 90% and TB-related deaths by 95% between 2015 - 2035. We determined the trend of case notification rates (CNRs) and treatment outcomes of TB cases with and without HIV co-infection in rural Uganda to provide an interim evaluation of progress towards this global target in rural settings. METHODS: We extracted retrospective programmatic data on notified TB cases and treatment outcomes from 2015 - 2019 for eight districts in rural Uganda from the District Health Information System 2. We estimated CNRs as the number of TB cases per 100,000 population. Treatment success rate (TSR) was calculated as the sum of TB cure and treatment completion for each year. Trends were estimated using the Mann-Kendall test. RESULTS: A total of 11,804 TB cases, of which 5,811 (49.2%) were HIV co-infected, were notified. The overall TB CNR increased by 3.7-fold from 37.7 to 141.3 cases per 100,000 population in 2015 and 2019 respectively. The increment was observed among people with HIV (from 204.7 to 730.2 per 100,000, p = 0.028) and HIV-uninfected individuals (from 19.9 to 78.7 per 100,000, p = 0.028). There was a decline in the TSR among HIV-negative TB cases from 82.1% in 2015 to 63.9% in 2019 (p = 0.086). Conversely, there was an increase in the TSR among HIV co-infected TB cases (from 69.9% to 81.9%, p = 0.807). CONCLUSION: The CNR increased among people with and without HIV while the TSR reduced among HIV-negative TB cases. There is need to refocus programs to address barriers to treatment success among HIV-negative TB cases.

Associations Between Mobility, Food Insecurity, and Transactional Sex Among Women in Cohabitating Partnerships: An Analysis From 6 African Countries 2016-2017.

BACKGROUND: Mobile women are at risk of HIV infection in sub-Saharan Africa, although we lack evidence for HIV risk among women in mobile partnerships, especially in the context of household food insecurity, a growing concern in the region. SETTING: Women aged 15-59 years with a cohabitating male partner who participated in population-based HIV impact assessment surveys in Eswatini, Lesotho, Namibia, Tanzania, Uganda, and Zambia. METHODS: We evaluated the association between women's and their partner's mobility (being away from home for more than 1 month or staying elsewhere) and transactional sex (selling sex or receiving money or goods in exchange for sex). We examined associations for effect measure modification by food insecurity level in the household in the past month. We used survey-weighted logistic regression, pooled and by country, adjusting for individual, partner, and household-level variables. RESULTS: Among women with a cohabitating male partner, 8.0% reported transactional sex, ranging from 2.7% in Lesotho to 13.4% in Uganda. Women's mobility [aOR 1.35 (95% CI: 1.08 to 1.68)], but not their partner's mobility [aOR 0.91 (0.74-1.12)], was associated with transactional sex. Food insecurity was associated with transactional sex independent of mobility [aOR 1.29 (1.10-1.52)]. Among those who were food insecure, mobility was not associated with increased odds of transactional sex. CONCLUSION: Food insecurity and women's mobility each increased the odds of transactional sex. Because transactional sex is associated with HIV risk, prevention programs can address the needs of mobile and food-insecure women, including those in cohabitating relationships.

National trends in prescription drug expenditures and projections for 2022.

PURPOSE: To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2022 in the United States, with a focus on the nonfederal hospital and clinic sectors. METHODS: Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2022 were reviewed-including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, generics, COVID-19 pandemic influence, and specialty drugs. For nonfederal hospitals, clinics, and overall (all sectors), estimates of growth of pharmaceutical expenditures in 2022 were based on a combination of quantitative analyses and expert opinion. RESULTS: In 2021, overall pharmaceutical expenditures in the US grew 7.7% compared to 2020, for a total of $576.9 billion. Utilization (a 4.8% increase), price (a 1.9% increase) and new drugs (a 1.1% increase) drove this increase. Adalimumab was the top drug in terms of overall expenditures in 2021, followed by apixaban and dulaglutide. Drug expenditures were $39.6 billion (a 8.4% increase) and $105.0 billion (a 7.7% increase) in nonfederal hospitals and in clinics, respectively. In clinics and hospitals, new products and increased utilization growth drove growth, with decreasing prices for both sectors acting as an expense restraint. Several new drugs that are likely to influence spending are expected to be approved in 2022. Specialty and cancer drugs will continue to drive expenditures along with the evolution of the COVID-19 pandemic. CONCLUSION: For 2022, we expect overall prescription drug spending to rise by 4.0% to 6.0%, whereas in clinics and hospitals we anticipate increases of 7.0% to 9.0% and 3.0% to 5.0%, respectively, compared to 2021. These national estimates of future pharmaceutical expenditure growth may not be representative of any particular health system because of the myriad of local factors that influence actual spending.

Randomised controlled trial on the effect of simethicone bowel preparation on rectal variability during image-guided radiation therapy for prostate cancer (SPoRT study).

INTRODUCTION: The purpose of this study was to assess whether simethicone reduces the rectal volume (RV) and gas volume (GV), to increase treatment accuracy and to decrease toxicity of prostate radiation therapy. METHODS: 30 patients were randomised to simethicone or no intervention. Cone-beam computed tomography (CBCT) scans were performed on Days 1-3 and weekly until completion of radiation. RV and GV were measured using volume delineation. Toxicity data were collected. RESULTS: 264 CBCTs were analysed. RV and GV were not significantly different in the simethicone group compared with the control group at each time point (P >0.05) after adjusting for Week 0 values as a covariate. The simethicone group showed an average reduction in RV and GV of 10% and 21%, respectively, compared with the control group (P >0.05). Standard deviations were calculated over 10 time points, which were grouped to represent the first 2-3 weeks of radiation therapy versus subsequent weeks. These were not significantly different between the simethicone and control group. However, there was a statistically significant decrease in the variability of RV at time points 6-10 compared with time points 1-5 within the simethicone group (P = 0.012), but no significant difference was found between these grouped time points in the control group (P = 0.581). The toxicity questionnaires showed no significant difference between the groups. CONCLUSIONS: Simethicone did not decrease the RV or GV overall. However, simethicone appeared to significantly decrease the RV variability from Week three onwards. This suggests that taking simethicone two to three weeks before starting radiation therapy may reduce RV variability, although a larger study is needed to confirm this.

Biology Beyond the Classroom: Experiential Learning Through Authentic Research, Design, and Community Engagement.

This paper introduces the collection of manuscripts from the symposium, "Biology Beyond the Classroom: Experiential Learning through Authentic Research, Design, and Community Engagement," presented at the 2021 annual meeting of the Society for Integrative and Comparative Biology. The following papers showcase innovative approaches for engaging undergraduate students in experiential science learning experiences. Specifically, we focus on three high-impact practices that allow students to take their learning outside of the classroom for increased relevance and authenticity: (1) Course-Based Undergraduate Research, (2) Digital Fabrication in Makerspaces, and (3) Service or Community-based Learning Opportunities. Although each topic is unique, all provide an alternative approach to the traditional lecture and have proven effective at appealing to diverse groups of students who are traditionally underrepresented in the Science, Technology, Engineering, and Mathematics workforce.